The adenoviruses cause enteric or respiratory infection in humans as well as in domestic and laboratory animals. The bovine adenoviruses (BAV) comprise at least nine serotypes divided into two subgroups. These subgroups have been characterized based on enzyme-linked immunoassays (ELISA), serologic studies with immunofluorescence assays, virus-neutralization tests, immunoelectron microscopy, by their host specificity and clinical syndromes. Subgroup 1 viruses include BAV 1, 2, 3 and 9 and grow relatively well in established bovine cells compared to subgroup 2 which includes BAV 4, 5, 6, 7 and 8.
BAV3 was first isolated in 1965 and is the best characterized of the BAV genotypes, containing a genome of approximately 35 kb (Kurokawa et al (1978) J. Virol. 28:212-218). Reddy et al. (1998, Journal of Virology, 72:1394) disclose nucleotide sequence, genome organization, and transcription map of BAV3. Reddy et al. (1999, Journal of Virology, 73: 9137) disclose a replication-defective BAV3 as an expression vector. BAV3, a representative of subgroup 1 of BAVs (Bartha (1969) Acta Vet. Acad. Sci. Hung. 19:319-321), is a common pathogen of cattle usually resulting in subclinical infection (Darbyshire et al. (1965), J. Comp. Pathol. 75:327-330), though occasionally associated with a more serious respiratory tract infection (Darbyshire et al., 1966 Res. Vet. Sci. 7:81-93; Mattson et al., 1988 J. Vet Res 49:67-69). Like other adenoviruses, BAV3 is a non-enveloped icosahedral particle of 75 nm in diameter (Niiyama et al. (1975) J. Virol. 16:621-633) containing a linear double-stranded DNA molecule. BAV3 can produce tumors when injected into hamsters (Darbyshire, 1966 Nature 211:102) and viral DNA can efficiently effect morphological transformation of mouse, hamster or rat cells in culture (Tsukamoto and Sugino, 1972 J. Virol. 9:465-473; Motoi et al., 1972 Gann 63:415-418). Cross hybridization was observed between BAV3 and human adenovirus type 2 (HAd2) (Hu et al., 1984 J. Virol. 49:604-608) in most regions of the genome including some regions near but not at the left end of the genome.
Porcine adenovirus (PAV) infection has been associated with encephalitis, pneumonia, kidney lesions and diarrhea. See Derbyshire (1992) In: “Diseases of Swine” (ed. Leman et al.), 7th edition, Iowa State University Press, Ames, Iowa. pp. 225-227. It has been shown that PAV is capable of stimulating both humoral response and a mucosal antibody responses in the intestine of infected piglets. Tuboly et al. (1993) Res. in Vet. Sci. 54:345-350. Cross-neutralization studies have indicated the existence of at least five serotypes of PAV. See Derbyshire et al. (1975) J. Comp. Pathol. 85:437-443; and Hirahara et al. (1990) Jpn. J. Vet. Sci. 52:407-409. Previous studies of the PAV genome have included the determination of restriction maps for PAV Type 3 (PAV-3) and cloning of restriction fragments representing the complete genome of PAV-3. See Reddy et al. (1993) Intervirology 36:161-168. In addition, restriction maps for PAV-1 and PAV-2 have been determined. See Reddy et al. (1995b) Arch. Virol. 140:195-200.
Nucleotide sequences have been determined for segments of the genome of various PAV serotypes. Sequences of the E3, pVIII and fiber genes of PAV-3 were determined by Reddy et al. (1995) Virus Res. 36:97-106. The E3, pVIII and fiber genes of PAV-1 and PAV-2 were sequenced by Reddy et al. (1996) Virus Res. 43:99-109, while the PAV-4 E3, pVIII and fiber gene sequences were determined by Kleiboeker (1994) Virus Res. 31:17-25. The PAV-4 fiber gene sequence was determined by Kleiboeker (1995) Virus Res. 39:299-309. Inverted terminal repeat (ITR) sequences for all five PAV serotypes (PAV-1 through PAV-5) were determined by Reddy et al (1995) Virology 212:237-239. The PAV-3 penton sequence was determined by McCoy et al. (1996) Arch. Virol. 141:1367-1375. The nucleotide sequence of the E1 region of PAV-4 was determined by Kleiboeker (1995) Virus Res. 36:259-268. The sequence of the protease (23K) gene of PAV-3 was determined by McCoy et al. (1996) DNA Seq. 6:251-254. The sequence of the PAV-3 hexon gene (and the 14 N-terminal codons of the 23K protease gene) has been deposited in the GenBank database under accession No. U34592. The sequence of the PAV-3 100K gene has been deposited in the GenBank database under accession No. U82628. The sequence of the PAV-3 E4 region has been determined by Reddy et al. (1997) Virus Genes 15:87-90. Vrati et al. (1995, Virology, 209:400-408) disclose sequences for ovine adenovirus.
At least 47 serotypes of human adenoviruses have been described. Reviews of the most common serotypes associated with particular diseases have been published. See for example, Foy H. M. (1989) Adenoviruses In Evans A S (ed). Viral Infections of Humans. New York, Plenum Publishing, pp 77-89 and Rubin B. A. (1993) Clinical picture and epidemiology of adenovirus infections, Acta Microbiol. Hung 40:303-323. The capsid of a human adenovirus demonstrates icosahedral symmetry and contains 252 capsomers. The capsomers consist of 240 hexons and 12 pentons with a projecting fiber on each of the pentons. The pentons and hexons are each derived from different viral polypeptides. The fibers, which are responsible for type-specific antibodies, vary in length among human strains. The hexons are group specific complement-fixing antibodies, whereas the pentons are especially active in hemgglutination (Plotkin and Orenstein, Vaccines, 3rd edition, W. B. Saunders Company Philadelphia, pp609-623). The fiber region assumes a homotrimeric conformation which is necessary for association of the mature fiber protein with the penton base in the formation of the adenovirus capsid. Fiber associates with penton base by virtue of non-covalent interactions between the amino terminus of the fiber trimer and a conserved domain within the penton base. It has been shown that the globular carboxyterminal knob domain of the adenovirus fiber protein is the ligand for attachment to the adenovirus primary cellular receptor (Krasnykh et al. (1996) Journal of Virology, 70:6839.). The distal, C-terminal domain of the trimeric fiber molecule terminates in a knob which binds with high affinity to a specific primary receptor. After binding, Arg-Gly-Asp (RGD) motifs in the penton base interact with cellular integrins of the αvβ3 and αvβ5 types which function as secondary receptors. This interaction triggers cellular internalization whereby the virion resides within the endosome. The endosome membrane is lysed in a process mediated by the penton base, releasing the contents of the endosome to the cytoplasm. During these processes, the virion is gradually uncoated and the adenovirus DNA is transported into the nucleus (Shayakhmetov et al. (2000) Journal of Virology 74:2567-2583).
For general background references regarding adenovirus and development of adenoviral vector systems, see Graham et al. (1973) Virology 52:456-467; Takiff et al. (1981) Lancet 11:832-834; Berkner et al. (1983) Nucleic Acid Research 11: 6003-6020; Graham (1984) EMBO J 3:2917-2922; Bett et al. (1993) J. Virology 67:5911-5921; and Bett et al. (1994) Proc. Natl. Acad. Sci. USA 91:8802-8806.
Adenoviruses generally undergo a lytic replication cycle following infection of a host cell. In addition to lysing the infected cell, the replicative process of adenovirus blocks the transport and translation host cell mRNA, thus inhibiting cellular protein synthesis. For a review of adenoviruses and adenovirus replication, see Shenk, T. and Horwitz, M. S., Virology, third edition, Fields, B. N. et al., eds., Raven Press Limited, New York (1996), Chapters 67 and 68, respectively.
The application of genetic engineering has resulted in several attempts to prepare adenovirus expression systems for obtaining vaccines. Examples of such research include the disclosures in U.S. Pat. No. 4,510,245 of an adenovirus major late promoter for expression in a yeast host; U.S. Pat. No. 4,920,209 on a live recombinant adenovirus type 7 with a gene coding for hepatitis-B surface antigen located at a deleted early region 3; European Patent 389 286 on a non-defective human adenovirus 5 recombinant expression system in human cells for HCMV major envelope glycoprotein; WO 91/11525 on live non-pathogenic immunogenic viable canine adenovirus in a cell expressing E1A proteins; and French Patent 2 642 767 on vectors containing a leader and/or promoter from the E3 region of adenovirus 2. U.S. Pat. Nos. 6,001,591 and 5,820,868 and International Publication Number WO 95/16048 disclose recombinant protein production in bovine adenovirus expression vector systems. U.S. Pat. No. 5,922,576 discloses systems for generating recombinant adenoviruses.
Krasnykh et al. (1996, Journal of Virology, 70:6839), Zabner et al. (1999) Journal of Virology, 73:8689), and Shayakhmetov et al. supra report generation of human adenovirus vectors with modified fiber regions. Xu et al. (1998, Virology, 248:156-163) disclose an ovine adenovirus carrying the fiber protein cell binding domain of human Adenovirus Type 5.
The disclosure of all patents and publications cited herein are incorporated by reference in their entirety.